Antibodies, immunoglobulins, and other biological immune factors (referred to here collectively as antibodies), both natural and their synthetic analogues, are known therapeutic agents in humans and animals. Antibodies operate by binding (via non-covalent forces) between the antigen combining site on the antibody and a portion of the antigen called the antigenic determinant or epitope. Antibodies are capable of high degrees of specificity. For example, the field of monoclonal antibodies has developed largely under the impetus of producing ever more specific and precise binding characteristics. However, this high specificity can lead to excessively limited binding attributes, where agents or antigens that are functionally identical do not react identically with the immunoreagent or immunotherapeutic. Cross-reactivity on the other hand, usually considered an error or failure to achieve binding specificity, is the reaction between an antigen and an antibody that was generated against a similar but different antigen. Controlled cross-reactivity may constructively be used to broaden the binding range of the antibody.
Colostrum has evolved naturally in mammals specifically to deliver its components to neonates to and through the gastrointestinal tract in a very concentrated low-volume form. Colostrum is known to contain antibodies such as IgA, IgG, and IgM. Other components of colostrum include lactoferrin, lysozyme, lactoperoxidase, complement, and proline-rich polypeptides (PRP). A number of cytokines (small messenger peptides that control the functioning of the immune system) are found in colostrum as well, including interleukins, tumor necrosis factor, chemokines, and others. Colostrum also contains a number of growth factors, such as insulin-like growth factors I, and II, transforming growth factors alpha, beta 1 and beta 2, fibroblast growth factors, epidermal growth factor, granulocyte-macrophage stimulating growth factor, platelet-derived growth factor, vascular endothelial growth factor, and colony-stimulating factor-I.
The antibodies and cofactors in colostrum can, through breast feeding provide a passive immunity to the recipient. Normally antibodies and cofactors are passed to the neonate from the mother and provide the first protection against pathogens. Growth factors also stimulate the development and repair of the gut.
One condition that could be addressed by using passive immunity is diarrhea. Diarrhea is caused mainly by the ingestion of pathogens. According to the World Health Organization (WHO), eighty-eight percent of cases diarrhea worldwide are attributable to unsafe water, inadequate sanitation or insufficient hygiene. These cases result in about 1.5 million deaths each year, most being the deaths of children. (Pruss-Urstun et al., Safer water, better health: costs, benefits and sustainability of interventions to protect and promote world health. World Health Organization, Geneva, 2008. ISBN 978 92 4 1596435).
Of particular global concern are the instances of infectious diarrhea in the developing world, which are a cause of tremendous ongoing morbidity and mortality, particularly in the pediatric population. For example, India has one of the highest infant mortality rates in the world according to a 2009 United Nations Human Development report. For example, Save the Children, a global non-profit, reports that one child dies every 15 seconds in India, and 90% of these deaths are due to preventable diseases, such as diarrhea. Rotavirus and measles vaccines, handwashing with soap, improved drinking water supply and community-wide sanitation are recommended by WHO for the prevention of diarrhea; however, these measures are not effective to treat the disease.
Standard treatment protocol in much of the world for pediatric diarrhea includes a concomitant administration of antibiotics and oral rehydrative therapy. For many reasons, antibiotics are a prescription drug. Antibiotics are not effective in the treatment of viral infection. For example, rotavirus is estimated to cause about 40 percent of all hospital admissions due to diarrhea among children under five years of age worldwide. (Weekly Epidemiological Record, vol. 83, no. 47, 21 Nov. 2008). The inappropriate use of antibiotics can promote resistant strains of bacteria. Conversely, the infection may be caused by a resistant strain of bacteria. Even under the best of circumstances, use of an appropriate antibiotic may take several days to reduce the severity of the symptoms of diarrhea.
Another disadvantage of antibiotics is that administration can induce the destruction of both pathogenic and benign bacteria found in the GI tract which can further result in release of endotoxic lipopolysaccharides. (Holzheimer, The significance of endotoxin release in experimental and clinical sepsis in surgical patients—evidence for antibiotic-induced endotoxin release? Infection. 1998 March-April; 26(2):77-84). These endotoxins have a host of adverse systemic effects including fever, changes in white blood cell counts, disseminated intravascular coagulation, hypotension, shock and death, malabsorption; in fact, the direct injection of fairly small doses of endotoxin results in death in most mammals. Todar K. Bacterial Endotoxin. Textbook of Bacteriology. 2008. textbookofbacteriology.net.
According to WHO, oral rehydration therapy and zinc with continued feeding, including breastfeeding, is recommended for treatment of childhood diarrhea. Zinc syrup or zinc-fortified oral rehydration solution (ORS, 40 mg/L) is typically employed at a dose of about 15 to 30 mg per day. Zinc is inexpensive, but has modest efficacy. Zinc syrup results in only about a 25 percent reduction in duration of acute diarrhea, and a 40 percent reduction in treatment failure or death. (Bhutta et al. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. The American Journal of Clinical Nutrition. 2000; 72(6): 1516-22). One study evaluated the efficacy and safety of a zinc-fortified (40 mg/L) ORS among 1,219 children with acute diarrhea. Clinical outcomes among the zinc-fortified ORS group were modestly improved, compared with those for the control group, who received standard ORS only. In that study, the total number of stools was lower among the zinc-ORS group compared with the total number for the control group. No substantial effect on duration of diarrhea or risk for prolonged diarrhea was noted. (Bahl R, Bhandari N, Saksena M, et al. Efficacy of zinc-fortified oral rehydration solution in 6- to 35-month-old children with acute diarrhea. J Pediatr 2002; 141:677-82).
It is known that antibiotics are ineffective to treat a viral infection, such as a rotavirus infection. Other interventions have limited effectiveness. Additionally, appropriate diagnostic tools to distinguish the cause of diarrhea are not always readily available or affordable.
Clearly a rapid, effective and economical alternative for the treatment of undifferentiated diarrhea is desirable. There remains a need for effective, economical compositions and methods for treatment of diarrhea and enteric infections in broad-spectrum, undifferentiated, or mixed clinical applications.